| 1. |
- Ebrahimi-Fakhari, Darius, et al.
(författare)
-
Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia
- 2020
-
Ingår i: Brain. - OXFORD ENGLAND : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 143:10, s. 2929-2944
-
Tidskriftsartikel (refereegranskat)abstract
- Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0-49.3 years). While the mean age at symptom onset was 0.8 +/- 0.6 years [standard deviation (SD), range 0.2-5.0], the mean age at diagnosis was 10.2 +/- 8.5 years (SD, range 0.1-46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 +/- 5.1 years, SD) and later tetraplegia (mean age: 16.1 +/- 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 +/- 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 +/- 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an 'AP-4 deficiency syndrome'. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.
|
|
| 2. |
- Faghihi, Mohammad Ali
(författare)
-
Regulation of gene expression by non-protein-coding RNAs
- 2009
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The human genome sequencing projects revealed that the human genome contains over 3 billion DNA base pairs, but only 20,000 25,000 protein-coding genes. In fact, only about 1.2% of the genome codes for proteins. Surprisingly, the number of human genes seems to be almost equal to lower mammals like rodents, and less than a factor of two greater than that of many much simpler organisms, such as the roundworm and the fruit fly. On the other hand, recent studies have revealed that eukaryotic genomes are almost entirely transcribed, generating an enormous number of non-protein-coding RNAs (ncRNAs). Thus there may be a vast reservoir of biologically meaningful ncRNAs that greatly exceed the 1.2% of the genome that corresponds to conventional protein coding genes. Several classes of functional ncRNAs have been identified in recent years. One prominent and complex class of ncRNAs is natural antisense transcripts (NATs). NATs are RNA molecules transcribed from the opposite strand of conventional genes often overlapping in part with mature sense mRNA. Indeed a large fraction of NATs is expressed in specific regions of the brain, supporting involvement of these ncRNAs in sophisticated regulatory brain functions as well as in complex neurological disorders. Recent research on NATs, including several large-scale expression-profiling studies, has conclusively established the existence of NATs in eukaryotic genomes. In fact, the consensus opinion is that natural antisense transcripts, most of which represent ncRNAs, occur abundantly in the mammalian genome. However, there are many unanswered questions that still exist concerning NATs biological functions and their heterogeneous mode of actions in various cells. For instance, what fraction of NATs may have functional significance, and how many different regulatory mechanisms may exist for these RNA molecules? NATs appear to be utilizing various cellular pathways, but it is still not clear which intrinsic properties of natural antisense RNA molecules or extrinsic features, such as protein interactions, cellular and developmental context are decisive for any given pathway. How is the expression of these ncRNAs regulated in various cells, and what are the extrinsic factors that affect the regulatory output of antisense RNA transcripts? Based on what we know about the broad expression of NATs in different tissues and cell types, and their varied proposed functions, NATs appear to be a heterogeneous group of regulatory RNAs with a wide variety of biological roles. During the course of my studies, I initially tried to uncover some general aspects of NAT-mediated regulation of gene expression. Thereafter I have investigated, in further detail, the functional significance of a number of these regulatory RNA elements. I have also reviewed all the reported cases of NATs and summarized them in the introduction section of my thesis. In conclusion, I found that there are widespread occurrences of NATs in mammalian genomes and that many of these regulatory elements are indeed functionally relevant in controlling conventional (sense) gene expression. Considering tissue- and cell type-specific expression patterns of NATs and their heterogeneous proposed functions, it seems that we have, so far, only touched parts of an elephant in the dark. The big picture, in the light of future studies, probably will include these parts, but it could be dissimilar to our current understanding. My work, like any other scientific project, has generated many more questions than answers. Several other Ph.D. assignments are needed to address these questions and to generate more questions for future projects and this is the nature of growing sciences.
|
|
| 3. |
- Gidlöf, Olof, et al.
(författare)
-
Extracellular Uridine Triphosphate and Adenosine Triphosphate Attenuate Endothelial Inflammation through miR-22-Mediated ICAM-1 Inhibition.
- 2015
-
Ingår i: Journal of Vascular Research. - : S. Karger AG. - 1423-0135 .- 1018-1172. ; 52:2, s. 71-80
-
Tidskriftsartikel (refereegranskat)abstract
- Adenosine and uridine triphosphate (ATP and UTP) can act as extracellular signalling molecules, playing important roles in vascular biology and disease. ATP and UTP acting via the P2Y2-receptor have, for example, been shown to regulate endothelial dilatation, inflammation and angiogenesis. MicroRNAs (miRNAs), a class of regulatory, short, non-coding RNAs, have been shown to be important regulators of these biological processes. In this study, we used RNA deep-sequencing to explore changes in miRNA expression in the human microvascular endothelial cell line HMEC-1 upon UTP treatment. The expression of miR-22, which we have previously shown to target ICAM-1 mRNA in HMEC-1, increased significantly after stimulation. Up-regulation of miR-22 and down-regulation of cell surface ICAM-1 were confirmed with qRT-PCR and flow cytometry, respectively. siRNA-mediated knockdown of the P2Y2-receptor abolished the effect of UTP on miR-22 transcription. Leukocyte adhesion was significantly inhibited in HMEC-1 following miR-22 overexpression and treatment with UTP/ATP. In conclusion, extracellular UTP and ATP can attenuate ICAM-1 expression and leukocyte adhesion in endothelial cells through miR-22. © 2015 S. Karger AG, Basel.
|
|
